Psychedelics in the treatment of unipolar mood disorders : a systematic review, James J.H. Rucker et al., 2016

Psychedelics in the treatment of unipolar mood disorders : a systematic review

James J.H. Rucker, Luke A. Jelen, Sarah Flynn, Kyle D. Frowde and Allan H. Young

Journal of Psychopharmacology, 2016, 1-10

DOI: 10.1177/0269881116679368


Unipolar mood disorders, including major depressive disorder and persistent depressive disorder (dysthymia), confer high rates of disability and mortality and a very high socioeconomic burden. Current treatment is suboptimal in most cases and there is little of note in the pharmaceutical development pipeline. The psychedelic drugs, including lysergic acid diethylamide and psilocybin, were used extensively in the treatment of mood disorders, and other psychiatric conditions, before their prohibition in the late 1960s. They are relatively safe when used in medically controlled environments, with no reported risk of dependence. Here, we present a systematic review of published clinical treatment studies using psychedelics in patients with broadly defined UMD, and consider their place in psychiatry. Whilst all of the included studies have methodological shortcomings, of 423 individuals in 19 studies, 335 (79.2%) showed clinician-judged improvement after treatment with psychedelics. A recently completed pilot study in the UK favours the use of psilocybin with psychological support in treatment resistant depressive disorder. The evidence overall strongly suggests that psychedelics should be re-examined in modern clinical trials for their use in unipolar mood disorders and other non-psychotic mental health conditions.

Keywords : Depression, dysthymia, psychedelics, psilocybin, LSD



Unipolar mood disorders (UMD), including major depressive disorder (MDD) and persistent depressive disorder (PDD; previously known as dysthymia), are common psychiatric disorders associated with high morbidity, high socio-economic burden and high rates of completed suicide (Greenberg et al., 1993; Harris and Barraclough, 1998; Kessler et al., 2003). The lifetime prevalence of MDD and PDD are conservatively estimated to be 6.7% and 3.6%, respectively (Waraich et al., 2004) and UMD is estimated to become the second leading cause of disability worldwide by 2020, second only to heart disease (Murray and Lopez, 1997). UMDs are frequently recurrent. PDD, by definition, lasts over 2 years and is often unremitting. Of those who have had an episode of MDD requiring psychiatric input, 80% will have another (Kessler et al., 2003) and the more episodes suffered the higher the likelihood of a further episode (Keller et al., 1982; Zis and Goodwin, 1979). In a large study using four successive medical treatment steps, 67% of patients eventually achieved remission (Rush and Trivedi, 2006), although the remainder, 33%, did not. Those who do not respond to multiple treatments have a poor prognosis that contributes to a disproportionate amount of socioeconomic burden, justifying calls for a research focus on novel therapeutic interventions (Cleare et al., 2015). Established but controversial therapies for resistant cases, such as electroconvulsive therapy and psychosurgery, are not effective in all cases, carry substantial stigma and the risk of significant side effects leads many patients to discount them as potential treatment options. Many pharmaceutical companies have ended research efforts into psychiatric disorders, and there are few novel agents in development (Hyman, 2013; Miller, 2010), leading some to look to history for inspiration. The dissociative drug ketamine has recently been investigated in this regard, however whilst there is some evidence for its use as a rapidly acting antidepressant, the effects appear to be transient, chronic usage has been associated with urinary tract problems and the drug has an established and concerning potential for abuse (Naughton et al., 2014).

Psychedelic compounds, particularly lysergic acid diethylamide (LSD) and psilocybin, were used and researched extensively in psychiatry before legal prohibition in 1967 (Grof, 2008). The drugs were initially noted to induce a temporary state of mind that was not dissimilar to psychosis. Whilst this suggested (and more formal research confirmed) that they were probably not useful for those with established psychotic disorders, or for those at high risk of developing them, patients suffering from so called ‘neurotic’ disorders, characterized by constrained, entrenched and often negative patterns of thought, feeling and behaviour, often reported new insights under the influence of psychedelics when taken in therapeutically supportive settings. Patients sometimes also described transformative states of mind that allegedly conferred long-lasting beneficial change (Grof, 2008), and which appeared to share some similarities with the states sought within the spiritual, religious and ceremonial uses of psychedelics, for which evidence stretches back to the dawn of recorded human history (Bruhn et al., 2002; Ott and Bigwood, 1978). As well as research in neuroses, covered in this review, an extensive research program on the use of LSD in the psychotherapeutic treatment of alcoholism was established, most notably in Canada (Dyck, 2006), and in the physical and existential pains experienced with terminal cancer at the Maryland Psychiatric Research Centre in North America (Grof and Halifax, 1977). The quality of many studies was suboptimal by modern standards, with the best quality research found in alcoholism. A recent meta-analysis of six good quality controlled trials of LSD treatment in alcoholism found that LSD treatment was favoured over placebo with an odds ratio of 1.96 (95% confidence interval
(CI) 1.36–2.84, p = 0.0003) (Krebs and Johansen, 2012).

Politically motivated and media-driven demonization of psychedelics in the 1960s and 1970s, alongside medical concern for the occasionally harmful sequelae of recreational use in psychologically destabilizing environments, has led to them being amongst the most stigmatized and legally restricted of all psychoactive compounds. However, they do not induce dependence (Brunton et al., 2011), and are physiologically (Gable, 2004) and psychologically (Cohen, 1960; Strassman, 1984) safe when used in medically controlled settings. Indeed, two separate, modern population studies have associated their use with a lower incidence of mental health problems and no increased risk of psychosis (Hendricks et al., 2015; Johansen and Krebs, 2015). They remain classified under Schedule I of the UN classification of drugs, severely restricting their use in research and entirely preventing their use in medical practice, a classification that has been recently questioned (Nutt et al., 2013; Rucker, 2015). Since the turn of the millennium, there has been an upsurge in interest in the mechanism of action of psychedelics and their therapeutic utility in a broad range of mental health problems, including UMDs. Investigations of their pharmacology (Passie et al., 2002; 2008), molecular neurobiology (Aghajanian and Marek, 1999; Halberstadt and Geyer, 2011; Moreno et al., 2011; Vollenweider and Kometer, 2010), neuroimaging correlates (Carhart-Harris et al., 2012; Carhart-Harris et al., 2016) and therapeutic mechanisms (Bogenschutz and Pommy, 2012; Loizaga- Velder and Verres, 2014; Maji et al., 2015; Tupper et al., 2015) have been published. The reviews of Nichols are particularly comprehensive (Nichols, 2004; 2016). Safety guidelines for the use of psychedelics in modern clinical research settings are also available (Johnson et al., 2008) and pilot clinical studies in anxiety associated with advanced cancer (Gasser et al., 2015; Grob et al., 2011), obsessive compulsive disorder (Moreno et al., 2006), tobacco (Johnson et al., 2014) and alcohol (Bogenschutz et al., 2015) addiction and cluster headaches (Sewell et al., 2006) have been completed over the last 10 years, with encouraging results. Some have also argued that psychedelics may confer new insights into the nature of psychotic disorders such as schizophrenia (González-Maeso and Sealfon, 2009) and wider theories of brain function (Carhart-Harris and Friston, 2010).

In this paper, we systematically collated the pre-prohibition literature on the therapeutic use of psychedelics on broadly defined unipolar mood disorder, within which we include contemporary depressive disorder with co-morbid anxiety, as well as disorders grouped under the old-fashioned terms ‘neurotic’ and ‘psychoneurotic’ disorders. This is with the aim of evidencing the debate on whether these substances should be reinvestigated with the benefit of modern, more systematic trial methodology. Pre-prohibition literature is described and synthesized and this is used to inform a discussion on the benefits and challenges of integrating contemporary psychedelic research into modern clinical trial designs.